Cancer development is caused by genetic alterations affecting the function of a number of genes. To understand the molecular mechanisms, it is necessary search for the affected genes exhaustively. In this phased innovation project, a highly efficient and cost effective genetic approach to genome scale analysis of cancers will be developed. In phase I, the capacity and sensitivity of a high-throughput multiplex genotyping system will be developed so that each assay may include 300 markers with a sensitivity of using 1200 cells from paraffin-archive tissue. In phase II, 12,000 genetic markers consisting of single nucleotide polymorphisms will be incorporated into this genotyping system so that as few as 40 assays will be sufficient for typing these markers. This system will be used for identifying chromosomal regions that may harbor tumor suppressor genes exhaustively and for revealing at least part of the regions that may contain protooncogenes in breast cancer. To obtain a high resolution, 1,000 carcinoma specimens and 200 metastatic specimens with paired specimens with paired specimens with paired specimens among the invasive specimens will be analyzed. The results will be used to select a small set of markers in the identified in the identified regions. The selected markers will be incorporated in to the high-throughput genotyping system so that one or very few assays will be needed for the future studies covering most, if not all, chromosomal regions that may harbor TSGs and some of the regions containing protooncogenes. Success of this project will make the high-throughput techniques available for genome-scale analysis of cancers. This will make many large-scale genetic studies that may need hundreds of years to complete if the single marker-base assays is used,, but only or few years with this high-throughput approach. The success of the project will also generate highly simplified and affordable experimental procedures for genome-scale analysis of breast cancer, which currently is technically challenging and not affordable for many of the laboratories.